Inhibition of ERN1 modifies the hypoxic regulation of the expression of TP53-related genes in U87 glioma cells

Abstract Inhibition of ERN1 (endoplasmic reticulum to nuclei 1), the major signalling pathway of endoplasmic reticulum stress, significantly decreases tumor growth. We have studied the expression of tumor protein 53 (TP53)- related genes such as TOPORS (topoisomerase I binding, arginine/serine-rich, E3 ubiquitin protein ligase), TP53BP1 (TP53 binding protein 1), TP53BP2, SESN1 (sestrin 1), NME6 (non-metastatic cells 6), and ZMAT3 (zinc finger, Matrin-type 3) in glioma cells expressing dominantnegative ERN1 under baseline and hypoxic conditions. We demonstrated that inhibition of ERN1 function in U87 glioma cells resulted in increased expression of RYBP, TP53BP2, and SESN1 genes, but decreased expression of TP53BP1, TOPORS, NME6, and ZMAT3 genes. Moreover, inhibition of ERN1 affected hypoxia-mediated changes in expression of TP53-related genes and their magnitude. Indeed, hypoxia has no effect on expression of TP53BP1 and SESN1 in control cells, while resulted in increased expression of these genes in cells with inhibited ERN1 function. Magnitude of hypoxia-mediated changes in expression levels of RYBP and TP53BP2 was gene specific and more robust in the case of TP53BP2. Hypoxiamediated decrease in expression levels of TOPORS was more prominent if ERN1 was inhibited. Present study demonstrates that fine-tuning of the expression of TP53- associated genes depends upon endoplasmic reticulum stress signaling under normal and hypoxic conditions. Inhibition of ERN1 branch of endoplasmic reticulum stress response correlates with deregulation of p53 signaling and slower tumor growth.